It is well known that impaired neurotransmission, e.g. low neurotransmitter levels, is connected to mental diseases, such as depression and generalised anxiety disorder (GAD), increased susceptibility to stress and cognitive dysfunction.
Compounds that increase neurotransmitter levels in the brain and thus enhance their transmission, can exhibit antidepressant properties and exert beneficial effects on a variety of other mental disorders (Neurotransmitters, Drugs and Brain Function R. A. Webster (ed), John Wiley & Sons, New York, 2001, p. 187-211, 289-452, 477-498). The main neurotransmitters are serotonin, dopamine, noradrenaline (=norepinephrine), acetylcholine, glutamate and gamma-aminobutyric acid (GABA). Those neurotransmitters of particular relevance to mood-related disorders include serotonin, noradrenaline and dopamine, while glutamate and acetylcholine neurotransmission are involved in cognitive function. Enhanced or prolonged neurotransmission is achieved by increasing the concentration of the neurotransmitter in the synaptic cleft, through inhibition of re-uptake into the pre-synaptic nerve ending, or by preventing neurotransmitter catabolism by inhibition of degrading enzymes, such as monoamine oxidases (MAOs)-A and -B. Also of interest are the neuropeptides, such as calcitonin gene-related peptide (CGRP).
Antidepressants and Mood-Related Disorders
Tricyclic antidepressants (TCAs), such as imipramine, amitriptyline and clomipramine, inhibit the re-uptake of serotonin and noradrenaline. They are widely regarded as among the most effective antidepressants available, but they have a number of disadvantages because they additionally interact with muscarinic acetylcholine-, histamine- and serotonin-receptors. Side effects resulting from such activities include dry mouth, blurred vision, constipation and urinary retention, in addition to postural hypotension. Most importantly, TCAs are not safe when taken in overdose, frequently showing acute cardiotoxicity.
Another class of antidepressant drugs is the so-called SSRIs (selective serotonin re-uptake inhibitors), including fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine, that block the serotonin transporter (SERT), a high affinity sodium chloride-dependent neurotransmitter transporter that terminates serotonergic neurotransmission by re-uptake of serotonin. They have been proven as effective in the treatment of depression and anxiety as TCAs, but are usually better tolerated. These medications are typically started at low dosages and are increased until they reach a therapeutic level. A common side effect is nausea. Other possible side effects include decreased appetite, dry mouth, sweating, infection, constipation, tremor, yawning, sleepiness and sexual dysfunction.
In addition, compounds that prevent the catabolism of neurotransmitters more broadly by inhibiting MAOs-A and -B exhibit antidepressant effects. MAOs catalyse the oxidation of amine group-containing neurotransmitters such as serotonin, noradrenaline and dopamine.
Furthermore, modulators of neurotransmission can thus exert pleiotropic effects on mental and cognitive functions.
There is a need for compounds for the treatment or prevention of mental diseases and/or disorders which do not show the negative side effects of known antidepressants. Many patients are interested in alternative therapies which could minimise the side effects associated with high doses of drugs and yield additive clinical benefits. Severe depression is a long-lasting and recurring disease, which is usually poorly diagnosed. Furthermore, many patients suffer from mild or moderately severe depression. Thus, there is an increasing interest in the development of compounds, as well as pharmaceutical and/or dietary compositions, which may be used to treat mental diseases/disorders or to prevent the development of mental diseases/disorders, such as depression and dysthymia, in people at risk, to stabilise mood and achieve emotional balance.
Patients often suffer either as comorbidity to depression, or alone, from GAD, which is a highly prevalent anxiety condition and chronic illness in primary care (˜10% of patients) (Wittchen, et al 2005 Eur. Neuropsychopharm. 15:357-376). Patients present themselves to their primary care physician with multiple physical symptoms. GAD is characterised by chronic tension, and anxious worrying and tension (>6 months), which are disabling and uncontrollable, and accompanied by a characteristic hypervigilance syndrome (including restlessness, muscle tension and sleep problems). If untreated, GAD runs a chronic, fluctuating course and tends to become increasingly severe with age. GAD patients suffer from subsyndromal depression and contribute to the highest overall direct and indirect health economic burden of all anxiety and depressive disorders. Despite high GAD incidence, few sufferers are diagnosed, prescribed medication, or receive psychiatric referral; simple diagnostic tools to aid patient recognition and monitoring are needed. Regardless of specific diagnosis, physicians require effective GAD-symptom treatments. SSRIs, such as paroxetine, are effective for GAD treatment (Stocchi et al. 2003, J. Clin. Psych., 63(3):250-258). Also, systematic reviews and placebo-controlled RCTs (Randomised Clinical Trials) indicate that some SSRIs (escitalopram, paroxetine and sertraline), the SNRI (Selective Noradrenaline Reuptake Inhibitor) venlafaxine, some benzodiazepines (alprazolam and diazepam), the TCA, imipramine, and the 5-HT1A partial agonist, buspirone, are all efficacious in acute treatment. In general, the effect of treatment is often moderate and symptoms reappear when the treatment period is discontinued. Therefore, a continuous long-term treatment or prevention with compounds which have fewer side effects than SSRIs and can be taken over long time periods might be favourable over drug treatment.
Mood disorders and occupational stress can lead to sleep disorders, insomnia, low sleep quality and general disturbances in circadian rhythms (so-called biorhythms); such conditions are often chronic and persistent in nature. Also, dysregulation of circadian rhythms induced by long-haul flights (jet-lag) and shift-work can cause similar symptoms and distress. Therefore, treatment with dietary supplementation to maintain a normal circadian rhythm (that a human or animal is used to) and/or to alleviate and prevent symptoms associated with a disturbed circadian rhythm, such as impairment of cognitive function and memory and mental and physical fatigue, thus improving the overall quality of life and benefiting the vital energy of a person in need thereof, would be most desirable.
Headache and Migraine
The major causes of headache are: tension, migraine, eye strain, dehydration, low blood sugar and sinusitis. Headaches can be classified as primary or secondary headaches. The primary headache disorders, which are not associated with any pathological changes, include migraine, tension-related headaches and cluster headaches. Secondary headache disorders, i.e., those caused by a pathological condition, include any head pain of infectious-, neoplastic-, vascular-, drug-induced-, or idiopathic-origin. Primary headaches, such as migraine and cluster headaches, affect up to 20% of the world's population, with a substantial impact on quality of life. Such are characterised by recurrent unilateral headaches, accompanied by nausea, vomiting and photophobia.
During migraine, trigeminal ganglion nerves are activated and release the neuropeptide, CGRP, resulting in vasodilation and mast cell degranulation, with subsequent release of inflammatory agents. Sensitisation of the trigeminal neurones ensues and resulting nociceptive transmission to the CNS contributes to the pain, nausea and photophobia associated with migraine (see Durham and Russo (1999), J. Neurosci., 19 (9), 3423-3429). There is thus a clear association between headache and the release of CGRP; both migraine and cluster headaches have been shown to be associated with elevated plasma CGRP levels, which are restored to normal after pain has been alleviated.
Furthermore, activation of the trigeminovascular nociceptive pathway may be facilitated by low serotonergic activity (Hamel (2007), Cephalalgia, 27 (11):1293-1300), while treatment with the triptans (e.g. sumatriptan), which activate the 5-HT1B/1D receptor, can relieve an acute migraine attack by reducing CGRP levels (Edvinsson, L. et al 2007, CNS Neurol. Disord. Drug Targets, 6(4): 240-246). Additionally, small molecule CGRP antagonists, without cardiovascular side-effects, have been shown to be efficacious in treating migraine (Edvinsson, L., 2007, Expert Opin. Ther. Targets, 11 (9): 1179-88). Blockade of the CGRP receptor is also effective in the prevention and treatment of menopausal flushing.
Cognition, Learning and Memory
As mentioned above, maintenance and modulation of mood primarily involve the serotonin-, noradrenaline- and dopamine-neurotransmitter systems, while acetylcholine, acting on nicotinic and muscarinic receptors, plays a role in cognitive processes, including conscious awareness, attention and working memory. Cholinergic agonists are known to improve memory whereas antagonists, generally, impair memory. Importantly, in addition to the involvement of acetylcholine receptor systems in neuropsychiatric disorders, such as attention-deficit hyperactivity disorder, Alzheimer's- and Parkinson's-diseases, there is evidence for nicotinic receptor-mediated cognitive enhancement in non-psychiatric healthy humans, while increased cognitive impairment can occur following co-administration of a muscarinic- and a nicotinic-antagonist. Similarly, inhibition of acetylcholinesterase, the metabolising enzyme for acetylcholine, can be effective in treating cognitive deficits associated with Alzheimer's disease, in addition to improving cognitive performance in healthy subjects.
Furthermore, long-term potentiation (LTP), the term used to describe long-lasting enhancement of synaptic transmission and being widely considered to be one of the major mechanisms by which memories are formed and stored in the brain, primarily involves the N-methyl-D-aspartate (NMDA) receptor complex and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, both of which bind the major excitatory neurotransmitter, glutamate. In addition to glutamate, the NMDA receptor requires a co-agonist, glycine, in order to modulate receptor function. Glycine transporters (GlyT-1 and -2) play an important role in the termination of postsynaptic glycinergic actions and maintenance of low extracellular glycine concentrations, by reuptake of glycine into presynaptic nerve terminals or glial cells.
There is an increasing interest in the development of compounds, as well as nutraceutical compositions, that may be used to improve learning, memory and alertness, in both elderly and young people, individuals who need especially high memory and attention in their daily work, including students, construction workers, drivers, pilots, physicians, salespeople, executives, housewives, “high performance professionals” and people who are under mental or daily stress as well as persons who are prone to psychiatric instability, such as schizophrenia.
Thus, a compound or nutraceutical composition which enhances NMDA receptor function, enabling improvements in learning, memory and alertness, in addition to enhancing activity of serotonin, noradrenaline and dopamine, enabling improved mood, would be highly desirable.